Nicotinamide Riboside

Potential Benefits of Nicotinamide Riboside

• Extends lifespan [1-15]
• Produces anti-aging effects [16-23]
• Improves exercise performance [13, 22-26]
• Promotes weight loss [25, 27-36]
• Increases muscle mass and strength [13, 15, 17, 22, 37-40]
• Boosts cognitive health [41-58]
• Lowers the risk of cardiovascular disease [29, 59-71]
• Prevents cancer and treats side effects of chemotherapy [72-83]
• Lowers blood pressure [84-85]
• Improves symptoms of diabetes and lowers blood sugar levels [86-91]
• Lowers the risk of stroke and improves recovery [92-97]
• Improves kidney function [98-102]
• Improves eye health [103-109]

What is Nicotinamide Riboside?

Also known as niagen, nicotinamide riboside (NR) is an alternative form of vitamin B3. It exerts its anti-aging effects when the body converts it into nicotinamide adenine dinucleotide (NAD+), a helper molecule (coenzyme) that is present in all living cells. NAD+ is essential for several important biological processes including the conversion of food into energy, DNA repair, regulation of immune function, and regulation of the body’s internal clock. Boosting NAD+ levels in the body has been shown to produce several health benefits. [1] Nicotinamide riboside can be found in small amounts in fruits, vegetables, meat, and milk.

How Nicotinamide Riboside Works

The conversion of nicotinamide riboside into nicotinamide adenine dinucleotide (NAD+) allows the body to perform various important biological processes. This includes energy production from food, DNA repair, regulation of immune function, and regulation of the body’s internal clock.

Chemical Structure of Nicotinamide Riboside

Research on Nicotinamide Riboside

A. Extends Lifespan

Nicotinamide riboside is converted by the body into nicotinamide adenine dinucleotide (NAD+), a helper molecule (coenzyme) that is present in all living cells and is essential for a broad range of biological functions. To put it simply, nicotinamide riboside is required in order to boost the levels of NAD+ in the body. Studies show that increased NAD+ levels are associated with a longer lifespan. [1-5] This suggests that boosting NAD+ levels through nicotinamide riboside supplementation may help extend lifespan.

Another mechanism that is known to extend lifespan is through increasing sirtuin (SIRT) activity. Increased SIRT activity has been shown to stabilize telomeres (located at chromosomes ends) and attenuate age-related telomere shortening. [6] Interestingly, studies found that individuals with longer telomeres have a longer subsequent lifespan. [7-8] With increased SIRT1 activity, the telomeres are more stable and their length increases which in turn extends lifespan.

Nicotinamide riboside-mediated increase in NAD+ activates SIRT1, an enzyme that plays an integral role in the regulation of proteins involved in cellular metabolism and processes associated with longevity, inflammation, and stress. SIRT1 activation removes acetyl groups from transcriptional regulators such as FOXO1 (Forkhead box protein O1) and PGC-1alpha (Peroxisome proliferator-activated receptor-gamma coactivator). This in turn causes metabolic adaptation, a survival mechanism that decreases the resting metabolic rate (number of calories burned at rest). As a result, cells undergo a process called mitochondrial biogenesis, which involves the production of new mitochondria (the powerhouse of cells). Mitochondrial biogenesis is critical for increased longevity since mitochondrial dysfunction in cells is associated with various age-related diseases and a shorter lifespan. [9-10]

A number of studies support that nicotinamide riboside can positively affect longevity mechanisms:

1. In human and mice subjects with telomere disease, supplementation with the NAD precursor, nicotinamide riboside, improved NAD homeostasis, which in turn alleviated damage to the telomeres, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence. [11]
2. In mice, nicotinamide riboside improved gene function and extended the lifespan without calorie restriction. [12]
3. In a mouse model of muscular dystrophy, a condition characterized by the gradual weakening of the muscles, treatment with the NAD+ precursor nicotinamide riboside delayed muscle breakdown and increased lifespan. [13]
4. In mice, nicotinamide riboside supplementation increased lifespan by protecting against high-fat diet-induced metabolic abnormalities and activating SIRT1 and SIRT3. [14-15]

B. Produces Anti-Aging Effects

Nicotinamide riboside-mediated increase in NAD+ levels can slow down the signs of aging by preventing mitochondrial dysfunction, which contributes to cellular senescence (also known as biological aging), increased inflammation, decreased stem cell activity, reduced healing rate, and a decline in tissue and organ function. [16] By activating SIRT1, new and healthy mitochondria are formed through a process called mitochondrial biogenesis.

An increasing number of evidence supports the anti-aging effects of nicotinamide riboside:

1. In mice with mitochondrial dysfunction, oral administration of nicotinamide riboside increased mitochondrial numbers and prevented muscle abnormalities. [17]
2. In mice, the administration of nicotinamide riboside prevented noise-induced hearing loss and degeneration of ear cells, suggesting that increasing NAD+ levels can help age-related hearing loss. [18]
3. In a mouse model of amyotrophic lateral sclerosis (ALS), which is characterized by progressive degeneration of motor neurons, nicotinamide riboside supplementation delayed motor neuron degeneration and decreased markers of neuroinflammation in the spinal cord. [19]
4. In aged men, nicotinamide riboside supplementation at 1 gram per day for 21 days increased NAD+ levels and decreased the levels of circulating inflammatory cytokines in the aged muscle. [20]
5. The use of NAD+ precursors such as nicotinamide riboside has been proposed as a strategy for improving age-related decline physiological functions. [21]
6. In aged mice, nicotinamide riboside rapidly ameliorated the aging-triggered muscle degeneration resulting in increased strength and endurance. [22]
7. A study reported that nicotinamide riboside can play an important role in anti-aging therapy in humans, especially in the face skin anti-aging treatment. [23]

C. Improves Exercise Performance

NAD+ plays an integral role in energy production and regulation of a broad range of biological processes. One of the most important functions of NAD+ is generating a usable form of energy called adenosine triphosphate (ATP). By boosting NAD+ levels, nicotinamide riboside can also help increase energy levels which can improve exercise performance.

Studies suggest that nicotinamide riboside supplementation can help improve exercise performance:

1. In a mouse model of muscular dystrophy, a condition characterized by the gradual weakening of the muscles, treatment with nicotinamide riboside increased maximal running times and distances. [13]
2. In aged mice, nicotinamide riboside rapidly ameliorated the aging-triggered muscle degeneration which in turn prevented the development of exercise intolerance. [22]
3. Nicotinamide riboside supplementation decreased oxidative stress and improved physical performance in older men (evidenced by improved scores in the fatigue index) compared to younger men. [24]
4. In mice, nicotinamide riboside supplementation increased endurance performance. [25]
5. In mice with heart and muscle weakness caused by adenine nucleotide translocator isoform 1 (ANT1) deficiency, nicotinamide riboside alleviated exercise intolerance. [26]

D. Promotes Weight Loss

Nicotinamide riboside boosts NAD+ levels which in turn increases energy expenditure. As a result, the body does not store additional fat. Moreover, evidence suggests that increased NAD+ levels are associated with increased metabolism. [27] All of these mechanisms can help promote weight loss.

The fat-burning properties of nicotinamide riboside are backed by a number of studies:

1. In mice, nicotinamide riboside protected against high-fat diet-induced obesity by enhancing oxidative metabolism. [25]
2. In obese men and women, the administration of nicotinamide riboside at a dose of 1 gram per day for 6 weeks was associated with a reduction in the percentage of fat mass. [28]
3. In obese rats, treatment with nicotinamide riboside alone mitigated final body weight gain and reduced adiposity (visceral and subcutaneous). [29]
4. In mice fed with a high-fat diet, nicotinamide riboside treatment was sufficient to deflect weight gain by increasing energy expenditure. [30]
5. In obese rats under calorie restriction, nicotinamide riboside supplementation (400 mg/kg) for 4 weeks enhanced weight loss without altering muscle mass. [31]
6. Obese female mice fed with nicotinamide riboside had significantly reduced body weight gain and fat mass and increased metabolic rates, physical activity, and energy expenditure compared with mice fed with a high-fat/high-sucrose/high-cholesterol diet. [32]
7. Nicotinamide riboside supplementation in female mice enhanced postpartum weight loss and increased lactation and nursing behaviors. [33]
8. In mice on a moderate-fat diet, nicotinamide riboside supplementation at 30 mg/kg per diet increased the activity of peroxisome proliferators–activated receptor γ (PPARγ), a master regulator of fat cell formation. [34]
9. In mice, nicotinamide riboside protected against high-fat diet-induced metabolic abnormalities by activating SIRT1 and SIRT3. [35]
10. In mice, nicotinamide riboside supplementation at 400 mg/kg/day for 5 weeks reduced the abdominal visceral fat depots. [36]

E. Increases Muscle Mass and Strength

By boosting NAD+ levels, nicotinamide riboside can help attenuate the age-related decline in muscle mass and strength. This is because increased NAD+ levels are associated with enhanced ATP production and mitochondrial function and reduced muscle inflammation. [37] In addition, NAD+ is found to be a major player in skeletal muscle development and regeneration. [38]

Studies suggest that nicotinamide riboside can help prevent muscle degeneration and improve muscle health:

1. In a mouse model of muscular dystrophy, a condition characterized by the gradual weakening of the muscles, treatment with nicotinamide riboside delayed muscle breakdown. [13, 15]
2. In mice with mitochondrial dysfunction, oral administration of nicotinamide riboside prevented muscle abnormalities by increasing mitochondrial numbers. [17]
3. In aged mice, nicotinamide riboside rapidly ameliorated the aging-triggered muscle degeneration. [22]
4. In overweight and obese patients, nicotinamide riboside supplementation increased skeletal muscle and induced minor changes in body composition. [39]
5. In healthy overweight or obese men and women, nicotinamide riboside supplementation at 1000 mg per day for 6 weeks increased muscle mass. [40]

F. Boosts Cognitive Health

The ability of nicotinamide riboside to improve cognitive function can be attributed to its NAD+-boosting properties. NAD+ can help protect against brain disorders by decreasing the production of reactive oxygen species (ROS), which are linked to a wide array of medical maladies including neurodegenerative diseases. [41] NAD+ can also help prevent degeneration of nerve cells in the brain by regulating the activity of poly adenosine diphosphate-ribose polymerase 1 (PARP1). [42-43] Another mechanism that is important in boosting cognitive health is the ability of NAD+ to regulate the production of brain chemicals called neurotransmitters, such as dopamine, serotonin, and norepinephrine. These brain chemicals play an integral role in different cognitive functions such as memory, motivation, attention, mood, and emotions.

Studies show that nicotinamide riboside can be a therapeutic strategy in improving brain health:

1. A study showed that nicotinamide riboside supplementation protected brain neurons (nerve cells) from traumatic injury. [44]
2. In a mouse model of Alzheimer’s disease, nicotinamide riboside treatment restored cognitive function by preventing the production of abnormal protein structures in the brain called beta-amyloid, attenuating DNA damage, and decreasing neuroinflammation. [45-51]
3. In diabetic mice fed with a high-fat diet, nicotinamide riboside improved cognitive function and reduced brain inflammation by decreasing the levels of abnormal protein structures. [52]
4. In a patient with Parkinson’s disease, nicotinamide riboside ameliorated the loss of nerve cells in the brain and decline in motor function. [53]
5. In mice with decreased short-term memory function, the addition of nicotinamide riboside into the food of the subjects for 28 days alleviated cerebral small vessel disease (CSVD) by protecting the brain integrity and preventing neuroinflammation. [54]
6. In mice with mild cognitive impairment, nicotinamide riboside treatment for 10 weeks improved blood flow to the brain. [55]
7. A latest review of multiple studies found that oral nicotinamide riboside supplementation has been shown to be successful in multiple preclinical models of neurodegeneration and brain function. [56]
8. In mice with brain injury due to insufficient blood flow, nicotinamide riboside treatment reduced the loss of brain nerve cells and ultimately promoted the recovery of cognitive function. [57]
9. A study reported that nicotinamide riboside can protect against the degeneration of nerve cells in the brain. [58]

G. Lowers the Risk of Cardiovascular Disease

Nicotinamide riboside-mediated increase in NAD+ levels can help promote normal heart function and enhanced cardiac recovery from injury. It has been shown that NAD+ activates SIRT3 which is associated with the prevention of heart enlargement and scarring. [59-61] Moreover, the mitochondrial conservation effects of NAD+ are known to play an integral role in inhibiting heart failure. [62]

Studies show that nicotinamide riboside can help protect against heart disease:

1. In obese Wistar rats under caloric restriction, nicotinamide riboside reduced cardiometabolic risk factors by modulating cardiac oxidative stress. [29]
2. In obese rats, nicotinamide riboside supplementation increased antioxidant capacity which in turn reduced the risk of cardiovascular disease. [63]
3. In a mouse model of dilated cardiomyopathy, nicotinamide riboside preserved cardiac function. [64]
4. A study showed that modulating NAD+ levels through nicotinamide riboside supplementation can help prevent heart disease. [65]
5. In mice with heart dysfunction, nicotinamide riboside reduced the levels of inflammatory cytokines and alleviated oxidative stress, heart enlargement, and cardiac dysfunction. [66]
6. In patients with heart failure with preserved ejection fraction, nicotinamide riboside improved heart function and lowered the risk of related deaths. [67]
7. In mice with heart injury due to insufficient blood flow, nicotinamide riboside suppressed scarring of the heart muscle and prevented the death of cardiac cells. [68]
8. In mice with chronic pressure overload in the heart, nicotinamide riboside protected against cardiac dysfunction and prevented heart enlargement. [69]
9. In mice receiving chemotherapy, nicotinamide riboside prevented doxorubicin-induced cardiotoxicity. [70]
10. In diabetic mice, nicotinamide riboside promoted mitochondrial fusion which in turn reduced the death of heart cells. [71]

H. Prevents Cancer and Treats Side Effects of Chemotherapy

Cancer cells usually exhibit mitochondrial respiration malfunction and increased glucose uptake – both of these mechanisms can be prevented by increasing NAD+ levels. [72] In addition, increased NAD+ levels are known to boost the activity of SIRT1 and SIRT6, both of which are known to exert anti-tumor effects. [73-74] This suggests that nicotinamide riboside-mediated increase in NAD+ levels can help inhibit cancer growth.

The anti-cancer properties of nicotinamide riboside and its ability to treat the side effects of chemotherapy are backed by a number of studies:

1. A study showed that nicotinamide riboside has the potential to be used in cancer prevention and therapy. [75]
2. A study also showed that nicotinamide riboside can be a promising approach for skin cancer prevention. [76]
3. A study reported that nicotinamide riboside can inhibit the growth of cancer cells via SIRT1 activation. [77]
4. In mice with cancer of the mucus-secreting gland cells, nicotinamide riboside mitigated muscle wasting associated with the disease. [78]
5. In tumor-bearing rats, once daily oral administration of 200 mg/kg nicotinamide riboside relieved peripheral neuropathy (nerve damage) caused by the chemotherapeutic drug paclitaxel and enhanced the suppression of tumor growth. [79-80]
6. In immune-deficient mice receiving cancer therapy, nicotinamide riboside improved survival by 80% and increased the production of immune system cells. [81]
7. In a mouse model of lung cancer, nicotinamide riboside alleviated nerve damage caused by the chemotherapeutic drug cisplatin via SIRT2 activation. [82]
8. In animal models of cancer, nicotinamide riboside administration prevented heart muscle injury caused by the chemotherapeutic drug doxorubicin. [83]

I. Lowers Blood Pressure

Nicotinamide riboside can also be beneficial in people with hypertension because of its blood pressure-lowering effects. By boosting NAD+ levels, SIRT1 activation occurs which in turn increases the production of nitric oxide, a substance that helps widen blood vessels (vasodilation) to allow an increase in blood flow. This process reduces the pressure within the blood vessels.

Studies report that nicotinamide riboside has anti-hypertensive properties:

1. In healthy, middle-aged-older adults, nicotinamide riboside supplementation reduced blood pressure and increased NAD+ levels. [84]
2. In hypertensive rats, nicotinamide riboside supplementation prevented age-related increase in blood pressure. [85]

J. Improves Symptoms of Diabetes and Lowers Blood Sugar Levels

Nicotinamide riboside can also benefit people suffering from the unpleasant symptoms of diabetes and high blood sugar levels. It does this by boosting the levels of NAD+ which in turn enhances the body’s response to the blood sugar-lowering effects of the hormone insulin.

Evidence shows that nicotinamide riboside has anti-diabetic effects:

1. In mice with type 2 diabetes, nicotinamide riboside supplementation prevented the development of type 2 diabetes and nerve damage. [86]
2. In mice, a high dose of dietary nicotinamide riboside prevented blood sugar intolerance. [87]
3. In overweight and obese patients, nicotinamide riboside supplementation increased skeletal muscle and induced minor changes in body composition and blood sugar. [88]
4. In a rodent model of obesity and type 2 diabetes, nicotinamide riboside improved blood sugar metabolism by correcting insulin resistance. [89]
5. In a rodent model of type 2 diabetes, nicotinamide riboside ameliorated liver inflammation. [90]
6. In mice with type 2 diabetes and severe insulin resistance, nicotinamide riboside greatly reduced non-fasting and fasting blood glucose, weight gain, and fat deposition in the liver while protecting against diabetic neuropathy (nerve damage). [91]

K. Lowers the Risk of Stroke and Improves Recovery

NAD+ is essential for brain health and may help protect against various brain injuries. Stroke is a condition wherein the blood supply to the brain is cut off or a blood vessel ruptures. NAD+ is known to improve blood circulation to the brain – a mechanism that may help prevent stroke. Since nicotinamide riboside boosts NAD+ levels, it may offer protective effects against stroke.

A good deal of evidence shows that nicotinamide riboside can help lower the risk of stroke and improve recovery through different mechanisms:

1. Studies found that nicotinamide riboside lowers the risk of stroke by protecting the nerve cells in the brain against various forms of injury or damage. [92-94]
2. In wild-type mice, nicotinamide riboside supplementation improved the recovery of the subjects from ischemic stroke (caused by inadequate blood supply). [95]
3. A study showed that nicotinamide riboside can be a therapeutic intervention for stroke rehabilitation. [96]
4. A study also showed that nicotinamide riboside has the capacity to restore the formation of new brain neurons, suggesting that it can help address the loss of neurons due to stroke. [97]

L. Improves Kidney Function

In acute kidney injury, substantial decreases in NAD+ levels are known to impair energy generation and affect the core function of the kidney. [98] In addition, decreased NAD+ levels also decrease sirtuin activity which contributes to the decline in kidney function. Thus, augmentation of NAD+ through nicotinamide riboside supplementation may help protect the kidneys and improve their health.

Nicotinamide riboside has been shown to play an essential role in maintaining optimal kidney function:

1. A study showed that nicotinamide riboside can help prevent the development of kidney disease by increasing NAD+ levels and sirtuin activity. [99]
2. A study found that boosting NAD+ levels via nicotinamide riboside administration ameliorated experimental kidney injury caused by inadequate blood flow. [100]
3. In dialysis patients, nicotinamide riboside supplementation reduced complications such as elevated phosphate levels. [101]
4. A study demonstrated that NAD+ precursors such as nicotinamide riboside may attenuate acute kidney injury by reducing oxidative stress and inflammation. [102]

M. Improves Eye Health

Nicotinamide riboside-mediated increase in NAD+ can also help protect against various eye disorders including the age-related decline in visual function. The modulation of sirtuin activity by NAD+ enhances retinal metabolism, reduces the death of eye cells, and improves vision. [103]

A number of convincing pieces of evidence suggest that nicotinamide riboside can help improve eye health:

1. In two mouse models of retinal ganglion cell damage, systemic treatment with nicotinamide riboside suppressed retinal inflammation. [104-105]
2. In a mouse model of light-induced retinal degeneration, nicotinamide riboside injections the day before and the morning of exposure to degeneration-inducing levels of light prevented programmed cell death and inflammation in the outer retina. [106]
3. In hydrogen peroxide-exposed human lens epithelial cell lines, nicotinamide riboside alleviated oxidative damage by targeting the MAPK and JAK2/Stat3 pathways. [107]
4. Preclinical studies suggest that nicotinamide riboside can be an effective therapeutic option to slow optic nerve degeneration in patients with primary open-angle glaucoma (POAG). [108-109]

Associated Side Effects of Nicotinamide Riboside

Nicotinamide riboside side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on nicotinamide riboside. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of nicotinamide riboside. Despite this, it was listed as a side effect associated with nicotinamide riboside even though these associated side effects are very uncommon.

Side effects associated with nicotinamide riboside may include the following:

• Bloating
• Diarrhea
• Fatigue
• Headache
• Indigestion
• Itching
• Nausea
• Sweating

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